4,4-Biarylpiperidine derivatives

ABSTRACT

The present invention relates to compounds of the formula I,  
                 
 
     wherein Z 1 , Z 2 , R 1 , R 2  and R 3  are defined as in the specification, pharmaceutical compositions containing such compounds the use of such compounds to treat neurological and gastrointestinal disorders.

BACKGROUND OF THE INVENTION

[0001] This invention relates to 4,4-biarypiperidine derivatives whichhave utility as ligands for opioid receptors.

[0002] In the study of opioid biochemistry, a variety of endogenousopioid compounds and non-endogenous opioid compounds has beenidentified. In this effort, significant research has been focused onunderstanding the mechanism of opioid drug action, particularly as itrelates to cellular and differentiated tissue opioid receptors.

[0003] Opioid drugs are typically classified by their bindingselectivity in respect of the cellular and differentiated tissuereceptors to which a specific drug species binds as a ligand. Thesereceptors include mu (μ), delta (δ) and kappa (κ) receptors.

[0004] At least three subtypes of opioid receptors (mu, delta and kappa)are described and documented in the scientific literature. All threereceptors are present in the central and peripheral nervous systems ofmany species including man. Activation of delta receptors producesantinociception in rodents and can induce analgesia in man, in additionto influencing motility of the gastrointestinal tract. (See Burks, T. F.(1995) in “The Pharmacology of Opioid Peptides”, edited by Tseng, L. F.,Harwood Academic Publishers).

[0005] The well known narcotic opiates such as morphine and its analogsare selective for the opioid mu receptor. Mu receptors mediateanalgesia, respiratory depression, and inhibition of gastrointestinaltransit. Kappa receptors mediate analgesia and sedation.

[0006] The existence of the opioid delta receptor is a relatively recentdiscovery which followed the isolation and characterization ofendogenous enkephalin peptides, which are ligands for the deltareceptor. Research in the past decade has produced significantinformation about the delta receptor, but a clear picture of itsfunction has not yet emerged. Delta receptors mediate analgesia, but donot appear to inhibit intestinal transit in the manner characteristic ofmu receptors.

[0007] U.S. Pat. No. 4,816,586, which issued on Mar. 28, 1989 to P. S.Portoghese, refers to various delta opioid receptor antagonists. Thesecompounds are described as possessing a unique opioid receptorantagonist profile, and include compounds that are highly selective forthe delta opioid receptor.

[0008] U.S. Pat. No. 4,518,711, which issued May 21, 1985 to V. J. Hrubyet al., describes cyclic, conformationally constrained analogs ofenkephalins. These compounds include both agonists and antagonists forthe delta receptor, and are said to induce pharmacological andtherapeutic effects, such as analgesia in the case of agonist species ofsuch compounds. The antagonist species of the disclosed compounds aresuggested to be useful in the treatment of schizophrenia, Alzheimer'sdisease, and respiratory and cardiovascular functions.

[0009] S. Goenechea, et al, in “Investigation of the Biotransformationof Meclozine in the Human Body,” J. Clin. Chem. Clin. Biochem., 1988,26(2), 105-15, describe the oral administration of a polyaryl piperazinecompound in a study of meclozine metabolization in human subjects.

[0010] In “Plasma Levels, Biotransformation and Excretion of Oxatomidein Rats, Dogs, and Man,” Xenobiotica, 1984, 15(6), 445-62, Meuldermans,W., et al. refer to a metabolic study of plasma levels,biotransformation, and excretion of oxatomide.

[0011] T. Iwamoto, et al, in “Effects of KB-2796, A New CalciumAntagonist, and Other Diphenylpiperazines on [³H]nitrendipine Binding”,Jpn. J. Pharmacol., 1988, 48(2), 241-7, describe the effect of apolyaryl piperazine as a calcium antagonist.

[0012] K. Natsuka, et al, in “Synthesis and Structure-ActivityRelationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazineDerivatives Having Narcotic Agonist and Antagonist Activity,” J. Med.Chem., 1987, 30 (10), 1779-1787, disclose racemates and enantiomers of1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazinederivatives.

[0013] European Patent Application No. 458,160, published on Nov. 27,1991, refers to certain substituted diphenylmethane derivatives asanalgesic and antiinflammatory agents, including compounds wherein themethylene bridging group (linking the two phenyl moieties) issubstituted on the methylene carbon with a piperidinyl or piperazinylgroup.

[0014] South African Patent Application No. 8604522, which was publishedon Dec. 12, 1986, refers to certain N-substituted arylalkyl andaryl-alkylene substituted amino-heterocyclic compounds, includingpiperdine derivatives, as cardiovascular, antihistamine, andanti-secretory agents.

[0015] European Patent Application No. 133,323, published on Feb. 20,1985, refers to certain diphenylmethyl piperazine compounds asnon-sedative antihistamines.

[0016] There is a continuing need in the art for improved opioidcompounds, particularly compounds which are free of addictive characterand other adverse side effects of conventional opiates such as morphineand pethidine.

[0017] The present inventor has discovered a novel class of4,4-biarylpiperidine derivatives that are potent and selective deltaopioid ligands and are useful for treatment of rejection in organtransplants and skin grafts, epilepsy, chronic pain, neurogenic pain,nonsomatic pain, stroke, cerebral ischemica, shock, head trauma, spinalcord trauma, brain edema, Hodgkin's disease, Sjogren's disease, systemiclupus erythematosis, gastrointestinal disorders such as gastritis,functional bowel disease, irritable bowel syndrome, functionaldiarrhoea, functional distention, nonulcerogenic dyspepsia and otherdisorders of motility or secretion, and emesis, acute pain, chronicpain, neurogenic pain, nonsomatic pain, allergies, respiratory disorderssuch as asthma, cough and apnea, inflammatory disorders such asrheumatoid arthritis, osteoarthristis, psoriasis and inflammatory boweldisease, urogenital tract disorders such as urinary incontinence,hypoxia (e.g., perinatal hypoxia), hypoglycemic neuronal damage,chemical dependencies and addictions (e.g., a dependency on, oraddiction to opiates, benzodiazepines, cocaine, nicotine or ethanol),drug or alcohol withdrawal symptoms, and cerebral deficits subsequent tocardiac bypass surgery and grafting.

SUMMARY OF THE INVENTION

[0018] This invention relates to compounds of the formula

[0019] wherein R¹ is hydrogen, (C₀-C₈)alkoxy-(C₀-C₈)alkyl-, wherein thetotal number of carbon atoms is eight or less, aryl, aryl-(C₁-C₈)alkyl-,heteroaryl, heteroaryl-(C₁-C₈)alkyl-, heterocyclic,heterocyclic-(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl-, or(C₃-C₇)cycloalkyl-(C₁-C₈)alkyl, wherein said aryl and the aryl moiety ofsaid aryl-(C₁-C₈)alkyl- are selected, independently, from phenyl andnapthyl, and wherein said heteroaryl and the heteroaryl moiety of saidheteroaryl-(C₁-C₈)alkyl- are selected, independently, from pyrazinyl,benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl,1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl,phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazolyl,isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl,tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl;and wherein said heterocyclic and the heterocyclic moiety of saidheterocyclic-(C₁-C₈)alkyl- are selected from saturated or unsaturatednonaromatic monocyclic or bicyclic ring systems, wherein said monocyclicring systems contain from four to seven ring carbon atoms, from one tothree of which may optionally be replaced with O, N or S, and whereinsaid bicyclic ring systems contain from seven to twelve ring carbonatoms, from one to four of which may optionally be replaced with O, N orS; and wherein any of the aryl, heteroaryl or heterocyclic moieties ofR¹ may optionally be substituted with from one to three substitutuents,preferably with one or two substutituents, independently selected fromhalo (i.e., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionallysubstituted with from one to seven (preferably with from zero to four)fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino, and whereinany of alkyl moieties in R¹ (e.g., the alkyl moieties of alkyl, alkoxyor alkylamino groups) may optionally be substituted with from one toseven (preferably with from zero to four) fluorine atoms;

[0020] R² is hydrogen, aryl, heteroaryl, heterocyclic, SO₂R⁴, COR⁴,CONR⁵R⁶, COOR⁴, or C(OH)R⁵R⁶ wherein each of R⁴, R⁵ and R⁶ is defined,independently, as R¹ is defined above, or R⁵ and R⁶, together with thecarbon or nitrogen to which they are both attached, form a three toseven membered saturated ring containing from zero to threeheterocarbons selected, independently, from O, N and S, and wherein saidaryl, heteroaryl, and heterocyclic are defined as such terms are definedabove in the definition of R¹, and wherein any of the aryl, heteroaryland heterocyclic moieties of R² may optionally be substituted with fromone to three substitutuents, preferably with one or two substutituents,independently selected from halo (i.e., chloro, fluoro, bromo or iodo),(C₁-C₆)alkyl optionally substituted with from one to seven (preferablywith from zero to four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl,amino, cyano, nitro, (C₁-C₆)alkoxy optionally substituted with from oneto seven (preferably with from zero to four) fluorine atoms,(C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino;

[0021] R³ is hydroxy, NHSO₂R⁷, C(OH)R⁷R⁸, fluorine or CONHR⁷, wherein R⁷and R⁸ are the same or different and are selected from hydrogen,(C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)alkoxy-(C₁-C₄)alkyl having atotal of 4 or less carbon atoms, and wherein any of the alkyl moietiesof R⁷ and R⁸ may optionally be substituted with from one to seven(preferably with from zero to four) fluorine atoms; and

[0022] Z¹ and Z² are selected, independently, from hydrogen, halo and(C₁-C₅)alkyl;

[0023] with the proviso that there are no two adjacent ring oxygen atomsand no ring oxygen atom adjacent to either a ring nitrogen atom or aring sulfur atom in any of the heterocyclic or heteroaryl moieties offormula I;

[0024] and the pharmaceutically acceptable salts of such compounds.

[0025] Preferred compounds of the formula I include those wherein R¹ iscyclopropylmethyl, 3-cyclohexylpropyl, 2-phenylethyl, 2-methylpentyl,p-methylbenzyl, 2,2,2-trifluoroethyl, or 1-methylpentyl.

[0026] Other examples of preferred compounds of the formula I are thosewherein R² is diethyl amide, methyl ethyl amide, a diethyl carbinol,tetrazole, or pyrazole.

[0027] Other examples of preferred compounds of the formula I are thosewherein R³ is hydroxy, fluoro, CONH₂, NHSO₂CH₃, or methoxy.

[0028] The compounds of formula I and their pharmaceutically acceptablesalts are opioid receptor ligands and are useful in the treatment of avariety of neurological and gastrointestinal disorders. Examples ofdisorders that can be treated with the compounds of formula I and theirpharmaceutically acceptable salts are rejection in organ transplants andskin grafts, epilepsy, chronic pain, neurogenic pain, nonsomatic pain,stroke, cerebral ischemica, shock, head trauma, spinal cord trauma,brain edema, Hodgkin's disease, Sjogren's disease, systemic lupuserythematosis, gastrointestinal disorders such as gastritis, functionalbowel disease, irritable bowel syndrome, functional diarrhoea,functional distention, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, acute pain, chronic pain, neurogenicpain, nonsomatic pain, allergies, respiratory disorders such as asthma,cough and apnea, inflammatory disorders such as rheumatoid arthritis,osteoarthritis, psoriasis and inflammatory bowel disease, urogenitaltract disorders such as urinary incontinence, hypoxia (e.g., perinatalhypoxia), hypoglycemic neuronal damage, chemical dependencies andaddictions (e.g., a dependency on, or addiction to opiates,benzodiazepines, cocaine, nicotine or ethanol), drug or alcoholwithdrawal symptoms, and cerebral deficits subsequent to cardiac bypasssurgery and grafting.

[0029] The present invention also relates to the pharmaceuticallyacceptable acid addition and base addition salts of compounds of theformula I. The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts. The chemical basesthat are used as reagents to prepare the pharmaceutically acceptablebase salts of this invention are those which form non-toxic base saltswith the acidic compounds of formula I. Such non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc.

[0030] The present invention also relates to the pharmaceuticallyacceptable base addition salts of compounds of the forumula I. Thesesalts are all prepared by conventional techniques. The chemical basesthat are used as reagents to prepare the pharmaceutically acceptablebase salts of this invention are those which form non-toxic base saltswith the acidic compounds of formula I. Such non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc.

[0031] For a review on pharmaceutically acceptable salts, see Berge etal., J. Pharm. Sci., 66, 1-19 (1977).

[0032] This invention also relates to a pharmaceutical composition fortreating a disorder or condition, the treatment or prevention of whichcan be effected or facilitated by modulating (i.e., increasing ordecreasing) binding to opioid receptors in a mammal, including a human,comprising an amount of a compound of the formula I, or apharmaceutically effective salt thereof, that is effective in treatingsuch disorder or condition and a pharmaceutically acceptable carrier.

[0033] This invention also relates to a method of treating a disorder orcondition, the treatment of which can be effected or facilitated bymodulating binding to opioid receptors in a mammal, comprisingadministering to a mammal in need of such treatment an amount of acompound of the formula I, or a pharmaceutically effective salt thereof,that is effective in treating such disorder or condition.

[0034] This invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from inflammatory diseasessuch as arthritis (e.g., rheumatoid arthritis and osteoarthritis),psoriasis, asthma, or inflammatory bowel disease, disorders ofrespiratory function such as asthma, cough and apnea, allergies,gastrointestinal disorders such as gastritis, functional bowel disease,irritable bowel syndrome, functional diarrhoea, functional distension,functional pain, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, stroke, shock, brain edema, headtrauma, spinal cord trauma, cerebral ischemia, cerebral deficitssubsequent to cardiac bypass surgery and grafting, urogential tractdisorders such as urinary incontinence, chemical dependencies andaddictions (e.g., addictions to or dependencies on alcohol, opiates,benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomaticpain, acute pain and neurogenic pain, systemic lupus erythematosis,Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organtransplants and skin grafts in a mammal, including a human, comprising aglutamate neurotransmission modulating effective amount of a compound ofthe formula I, or a pharmaceutically salt thereof, and apharmaceutically acceptable carrier.

[0035] This invention also relates to a method for treating a conditionselected from inflammatory diseases such as arthritis, psoriasis,asthma, or inflammatory bowel disease, disorders of respiratory functionsuch as asthma, cough and apnea, allergies, gastrointestinal disorderssuch as gastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distension, functional pain,nonulcerogenic dyspepsia and other disorders of motility or secretion,and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma,cerebral ischemia, cerebral deficits subsequent to cardiac bypasssurgery and grafting, urogential tract disorders such as urinaryincontinence, chemical dependencies and addictions (e.g., addictions toor dependencies on alcohol, opiates, benzodiazepines, nicotine, heroinor cocaine), chronic pain, nonsomatic pain, acute pain and neurogenicpain, systemic lupus erythematosis, Hodgkin's disease, Sjogren'sdisease, epilepsy and rejection in organ transplants and skin grafts, ina mammal, comprising administering to such mammal, including a human, anopioid receptor binding modulating effective amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof.

[0036] This invention also relates to a pharmaceutical composition fortreating a disorder or condition, the treatment of which can be effectedor facilitated by modulating binding to opioid receptors in a mammal,including a human, comprising an opioid receptor binding modulatingeffective amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] This invention also relates to a method for treating a disorderor condition, the treatment of which can be effected or facilitated bymodulating in a mammal, including a human, comprising administering tosuch mammal an opioid receptor binding modulating effective amount of acompound of the formula I or a pharmaceutically acceptable salt thereof.

[0038] This invention also relates to a method of treating a conditionselected from inflammatory diseases such as arthritis, psoriasis,asthma, or inflammatory bowel disease, disorders of respiratory functionsuch as asthma, cough and apnea, allergies, gastrointestinal disorderssuch as gastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distension, functional pain,nonulcerogenic dyspepsia and other disorders of motility or secretion,and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma;cerebral ischemia, cerebral deficits subsequent to cardiac bypasssurgery and grafting, urogential tract disorders such as urinaryincontinence, chemical dependencies and addictions (e.g., addictions toor dependencies on alcohol, opiates, benzodiazepines, nicotine, heroinor cocaine), chronic pain, nonsomatic pain, acute pain and neurogenicpain, systemic lupus erythematosis, Hodgkin's disease, Sjogren'sdisease, epilepsy and rejection in organ transplants and skin grafts ina mammal, comprising administering to a mammal in need of such treatmentan amount of a compound of the formula I that is effective in treatingsuch condition.

[0039] This invention also relates to a pharmaceutical composition fortreating a condition selected from inflammatory diseases such asarthritis, psoriasis, asthma, or inflammatory bowel disease, disordersof respiratory function such as asthma, cough and apnea, allergies,gastrointestinal disorders such as gastritis, functional bowel disease,irritable bowel syndrome, functional diarrhoea, functional distension,functional pain, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, stroke, shock, brain edema, headtrauma, spinal cord trauma, cerebral ischemia, cerebral deficitssubsequent to cardiac bypass surgery and grafting, urogential tractdisorders such as urinary incontinence, chemical dependencies andaddictions (e.g., addictions to or dependencies on alcohol, opiates,benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomaticpain, acute pain and neurogenic pain, systemic lupus erythematosis,Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organtransplants and skin grafts in a mammal, comprising an amount of acompound of the formula I that is effective in treating such conditionand a pharmaceutically acceptable carrier.

[0040] Unless otherwise indicated, the alkyl groups referred to herein,as well as the alkyl moieties of other groups referred to herein (e.g.,alkoxy), may be linear or branched, and they may also be cyclic (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear orbranched and contain cyclic moieties.

[0041] The term “alkoxy”, as used herein, means “—O-alkyl”, wherein“alkyl” is defined as above.

[0042] The term “alkylene”, as used herein, means an alkyl group havingtwo available binding sites (i.e., -alkyl-, wherein alkyl is defined asabove).

[0043] The term “treating” as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0044] Unless otherwise indicated, “halo” and “halogen”, as used herein,refer to fluorine, bromine, chlorine or iodine.

[0045] Compounds of the formula I may have chiral centers and thereforemay exist in different enantiomeric and diastereomic forms. Thisinvention relates to all optical isomers and all other stereoisomers ofcompounds of the formula I, and to all racemic and other mixturesthereof, and to all pharmaceutical compositions and methods of treatmentdefined above that contain or employ such isomers or mixtures.

[0046] Formula I above includes compounds identical to those depictedbut for the fact that one or more hydrogen or carbon atoms are replacedby isotopes thereof. Such compounds are useful as research anddiagnostic tools in metabolism pharmokinetic studies and in bindingassays. Specific applications in research include radioligand bindingassays, autoradiography studies and in vivo binding studies.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The compounds of formula I can be prepared according to themethods illustrated in Schemes 1-9 and discussed below. In the reactionschemes and discussion that follow, unless otherwise indicated, Z¹, Z²,R¹, R², and R³ and structural formula I are defined as above.

[0048] Scheme 1 illustrates a method for the preparation of compoundswith the general formula I wherein R³ is (C₁-C₆)alkoxy or fluorine, R²is CONR⁵R⁶ and R¹ is as defined above with the proviso that it is notattached to the piperidine nitrogen at a secondary alkyl carbon or anaryl group. Referring to Scheme 1, a bromobenzene derivative of formula0, wherein R³ is methoxy or fluorine, is cooled to −70° C. in drytetrahydrofuran, and then a solution of n-butyllithium is added to it.The resulting solution is then treated with N-benzylpiperidinone and thesolution is allowed to warm to room temperature to produce thecorresponding compound of formula 1.

[0049] Alternatively, the benzene derivative of formula 0 intetrahydrofuran can be treated with magnesium at a temperature fromabout 0° C. to the reflux temperature, preferably starting at roomtemperature for about three hours and then heating to reflux and lettingthe reaction proceed for another hour, after which N-benzylpiperidinoneis added to the mixture. The resulting solution is then stirred at atemperature ranging from about 0° C. to the reflux temperature,preferably at about room temperature, to produce the correspondingcompound of formula 1.

[0050] The compound of formula 1, produced by either of the abovemethods, in dichloroethane is then treated with phenol and aluminumchloride or another Lewis acid (e.g., boron trifluoride etherate), andthe resulting solution is stirred at a temperature ranging from about 0°C. to the reflux temperature, preferably at about the refluxtemperature, to produce the corresponding phenol derivative of formula2. The compound of formula 2 is then treated with trifluoromethanesulfonic anhydride or another suitable reagent such asN-phenyltrifluoromethanesulfonimide, in the presence of a base such aspyridine, triethylamine, another trialkyl amine, an alkali metal hydrideor an alkali metal carbonate, to form the trifluoromethane sulfonateester of formula 3. This reaction is typically performed indicloromethane at a temperature ranging from about 0° C. to the refluxtemperature, preferably at about room temperature.

[0051] The compound of formula 3 is placed under a carbon monoxideatmosphere at a pressure ranging from about 14 to 100 psi, in a solutionof dimethylsulfoxide and a lower alkanol such as methanol or ethanol,with a suitable trialkylamine base (e.g., triethylamine) and palladiumacetate with 1,3-bis(diphenylphosphino)propane (DPPP) or anothersuitable palladium ligand. Other suitable palladium catalysts such asbis(triphenylphosphine) palladium dichloride may also be used. Thisreaction is performed at temperatures ranging from about 20° C. to 100°C.

[0052] Treatment of the ester of formula 4 with an aluminum amide of aprimary or secondary amine, for example, diethyl amine, in a solventsuch as dichloroethane or toluene, at a temperature ranging from about20° C. to about the reflux temperature, preferably at about the refluxtemperature, yields the corresponding amide of formula 5. Variations inthe nature of the R¹ group on the piperidine nitrogen can be effected inthe following manner, as illustrated by process steps (5→6→7) inScheme 1. The compound of formula 5 is placed under a hydrogenatmosphere at pressures ranging from about 14 to 100 psi, in ethanol orother another solvent such as acetic acid or methanol, to produce thecorresponding compound of formula 6. This reaction is typically carriedout at a temperature from about 0° C. to about the reflux temperature,preferably at about room temperature.

[0053] Treatment of the compound of formula 6 with an aldehyde andsodium triacetoxyborohydride or another reducing agent (e.g., sodiumborohydride or sodium cyanoborohydride), in dichloromethane, 1,2dichloroethane or another suitable solvent such as methanol, ethanol ortoluene, at a temperature ranging from about 0° C. to 100° C.,preferably at about room temperature, yields the desired compound offormula 7.

[0054] Compounds of formula I wherein R¹ is a group that attaches to thepiperidine nitrogen via an aryl moiety or a primary or secondary alkylmoiety, can be prepared by treating the corresponding compound offormula 6 with an alkylating or arylating agent of the formula R¹X,wherein X is a leaving group such as chloro, bromo, iodo, triflate(OTf), mesylate (OMs) or tosylate (Ots), and sodium or potassiumcarbonate or another alkali metal carbonate or bicarbonate in a solventsuch as dimethylformamide, dichloromethane or 1,2 dichloroethane, at atemperature ranging from about 20° C. to 100° C., as shown below inScheme 2.

[0055] In connection with the definition of formula R¹X in the casewhere X is an aldehyde moiety (CHO), it is noted that the aldehydecarbon attaches to the piperidine nitrogen and thus R¹ would include anadditional carbon atom, which fact is reflected in Example 16 (reactantF→reactant G) where the designation R^(X)CHO was used.

[0056] Compounds of the general formula I where R³ is hydroxy can beprepared by deprotecting the corresponding alkyl ether of formula 7(wherein R¹⁰ is (C₁-C₆)alkyl) with boron tribromide in dicloromethane,or with aqueous hydrobromic acid and acetic acid, or with sodiumethanethiolate in dimethylformamide, at a temperature ranging from about0° C. to the reflux temperature, as shown in Scheme 3. Room temperatureis preferred when boron tribromide is used, the reflux temperature ispreferred when hydrobromic acid/acetic acid is used, and about 100° C.to about 120° C. is preferred when sodium ethanemethiolate is used.

[0057] Compounds of the general formula I where R³═CONHR can be preparedfrom the corresponding phenols of formula 9 as illustrated in Scheme 4below. This can be accomplished by formation of the triflate of formula10 using conditions identical to those used for the preparation ofcompounds of the formula 3 (Scheme 1). The compound of formula 10 isthen converted to the corresponding ester of formula 11 using conditionsidentical to those used in the preparation of esters of the formula 4(Scheme 1). Treatment of the compound of formula 11 with an aluminumamide of an amine in a solvent such as toluene or 1,2 dichloroethane, ata temperature ranging from about 0° C. to about the reflux temperature,preferably at about the reflux temperature, or treatment of the samewith a lithium amide in ether or tetrahydrofuran at a temperatureranging from about −78° C. to the reflux temperature, preferably atabout −78° C., yields the desired compound of formula I whereinR³═CONHR⁴ and R⁴ is (formula 12 below).

[0058] Alternatively, the carboxamide of formula 12 can be accessed byconversion of the triflate ester of formula 10 into the nitrile offormula 13 by treatment with zinc cyanide and a palladium catalyst suchas tetrakis triphenylphosphine palladium, in a solvent such asdimethylformamide, or toluene, at a temperature from about 0° C. toabout the reflux temperature, preferably at about the refluxtemperature. The nitrile of formula 13 can be converted into thecarboxamide of formula 12 by treatment with hydrogen peroxide and sodiumcarbonate in ethanol, at a temperature ranging from about 0° C. to aboutthe reflux temperature, preferably at about room temperature.

[0059] Compounds of the general formula I where R³ is NHSO₂R⁵ can beprepared, as illustrated in Scheme 5, by hydrolysis of the ester offormula 11 to the carboxylic acid of formula 14 by reacting it withlithium hydroxide or another alkali metal hydroxide in a mixture oftetrahydrofuran (THF) and water, at a temperature from about roomtemperature to about the reflux temperature. The compound of formula 14is then converted into the aniline of formula 15 by reaction withdiphenylphosphoryl azide in the presence of triethylamine or anothertrialkylamine base, in t-butanol at the reflux temperature, followed byacid hydrolysis with aqueous hydrochloric acid in ethyl acetate or withtrifluoroacetic acid in methylene chloride. The compound of the formula15 is then sulfonylated to produce the desired compound of formula 16with an aryl- or alkylsulfonyl chloride and pyridine triethylamine oranother trialkylamine base in dichloromethane, dichloroethane ortoluene, at temperatures from about 0° C. to about the refluxtemperature, preferably at about room temperature.

[0060] Compounds of the general formula I wherein R³ is methoxy, hydroxyor fluorine and R² is an aromatic or heteroaromatic moiety (referred toin Scheme 6 as compounds of the formula 17) can be prepared byorganometalic coupling of a compound of the formula 3 with an aryl andheteroaryl boronic acid, wherein aryl and heteroaryl are defined as inthe definitions of R¹ and R², in a solvent such as ethanol or toluene,in the presence of a of palladium catalyst such as tetrakistriphenylphosphine palladium and a trialkylamine base (e.g.,triethylamine) or alkali metal carbonate base, as shown below in Scheme6. This reaction is generally carried out at a temperature from aboutroom temperature to about the reflux temperature, preferably at aboutthe reflux temperature.

[0061] Compounds of the formula 1 wherein R² is tetrazoyl can beprepared, as illustrated in Scheme 7 below, by conversion of theappropriate triflate of formula 3 into the corresponding nitrile offormula 18. This can be accomplished by reacting the triflate compoundwith zinc cyanide and a palladium catalyst such as tetrakistriphenylphosphine palladium in a solvent such as dimethylformamide, ata temperature ranging from about 0° C. to about 100° C., preferably atabout the reflux temperature. The formation of the tetrazole proceeds bytreatment of the resulting nitrile with sodium or trimethylsilylazideand a catalytic amount of tin oxide in a solvent such asdimethylformamide, preferably at about the reflux temperature ortoluene, at a temperature ranging from about 20° C. to about the refluxtemperature. Alkylation of the tetrazole proceeds by reaction withtriethylamine or another trialkylamine base or an alkali metal hydride,alkoxide or carbonate, and with the appropriate compound of the formulaR⁶X wherein X is a leaving group such as chloro, bromo, iodo, triflate,mesylate or tosylate, in a solvent such as methanol, ethanol, ortetrahydrofuran, at temperatures ranging from about 0° C. to about thereflux temperature, preferably at about room temperature.

[0062] Compounds of the general formula I wherein R³ is fluoro ormethoxy and R² is a heterocycle such as oxazoline or thiazoline can beprepared, as illustrated in Scheme 8, from the appropriate carboxylicacid of formula 20, which can be prepared using conditions identical tothose used for the formation of the carboxylic acids of formula 12(Scheme 5). The carboxylic acid of formula 20 is first converted intothe corresponding acid chloride by reaction with oxalyl chloride orthionyl chloride and then treated with the appropriate amino alcohol ofthe formula NH₂C(R⁵)(R⁶)CH₂OH or amino thiol of formulaNH₂C(R⁵)(R⁶)CH₂S. Conversion to the acid chloride is generally carriedout neat or in a solvent such as dichloromethane or dichloroethane, at atemperature from about 0° C. to about the reflux temperature, preferablyat about the reflux temperature. Treatment with the appropriate aminoalcohol or amino thiol is generally carried out at similar temperaturesin a solvent such as dichloromethane or dichloroethame. Dehydrativecyclization using thionyl chloride, neat or in dichloromethane about thereflux temperature, or using trifluoromethane sulfonic anhydride andpyridine or a trialkyl amine such as triethylamine, in dichloromethane,dichloroethane or tetrahydrofuran, at a temperature ranging from about−78° C. to about the reflux temperature, preferably starting at about−78° C. and gradually warming to room temperature, yeilds the desiredcompound of formula I. This series of reactions is illustrated in Scheme8 for the preparation of compounds of the formula I wherein R³ is fluoroor methoxy and R² is 4,4-dimethyloxazolyl (formula 23 in Scheme 8).

[0063] Alternatively, compounds of the formula 23 can be prepared, asillustrated in Scheme 8A, by treatment of the appropriate amide offormula 7 (Scheme 1) with triflic anhydride, pyridine or a trialkylaminebase such as triethylamine, and the appropriate amino alcohol or aminothiol, as referred to in the preceding paragraph, in a solvent such asdichloromethane or dichloroethane, at a temperature from about −78° C.to about room temperature, preferably starting at −78° C. and slowlyallowing the reaction mixture to warm to room temperature.

[0064] Compounds of the general formula I where R³ is fluoro or methoxyand R² is a carbinol such as diethyl carbinol (referred to in Scheme 9as compounds of the formula 24 can be prepared, as illustrated in Scheme9, by treatment of the ester of formula 4 with an alkyl Grignard oralkyl lithium reagent, in a solvent such as ether or tetrahydrofuran, ata temperature ranging from about −78° C. to about the refluxtemperature, preferably starting at room temperature and heating toabout the reflux temperature.

[0065] Compounds of the general formula I where R² is a diazaoxazolering (e.g., compounds of the formula 27 in Scheme 10) can be prepared,as illustrated in Scheme 10, by treatment of the methyl ester of formula4 with hydrazine hydrate in methanol, at a temperature from about 0° C.to about the reflux temperature, preferably at about the refluxtemperature, to form the hydrazide of formula 25. Subsequent acylationwith an acid chloride and pyridine, triethylamine or anothertrialkylamine in a solvent such as dichloromethane, dichloroethane ortoluene, at a temperature from about 0° C. to about the refluxtemperature, preferably at about room temperature provides thecorresponding compound of formula 26. Cyclization can be accomplishedusing a reagent combination such as triphenylphospine/iodine andtriethylamine or another trialkylamine in a solvent such astetrahydrofuran, or toluene, at a temperature from about 0° C. to aboutthe reflux temperature, preferably at about room temperature or usingtriflic anhydride and pyridine or a trialkylamine in dichloromethane, ortetrahydrofuran, at a temperature from about −78° C. to about roomtemperature, preferably starting at −78° C. and gradually warming toroom temperature, or using thionyl chloride in dichloromethane, or neat,at a temperature from about room temperature to about the refluxtemperature, preferably at about the reflux temperature, to yield thedesired compound of formula 27.

[0066] The preferred method of making compounds of the formula I whereinR³ is OH, NHSO₂R⁷, C(OH)R⁷R⁸ or C(═O)NHR⁷ is to make the analogouscompounds wherein R³ is O—(C₁-C₆)alkyl and then derivative them usingstandards methods well known in art and illustrated in the foregoingschemes.

[0067] The starting materials used in the processes of Schemes 1-10 areeither commercially available, known in the literature, or readilyobtainable from commercially available or known compounds using methodsthat are well known in the art or described above.

[0068] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions will be conducted ata pressure from about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

[0069] The preparation of other compounds of the formula I notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0070] The compounds of the formula I that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. The acid that can be used to prepare thepharmaceutically acceptable acid addition salts of the base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such ashydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate,phosphate or acid phosphate, acetate, lactate, citrate or acid citrate,tartrate or bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such saltsmust be pharmaceutically acceptable for administration to animals, it isoften desirable in practice to initially isolate a compound of theformula I from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0071] Compounds of the formula that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.These salts are all prepared by conventional techniques. The chemicalbases that are used as reagents to prepare the pharmaceuticallyacceptable base salts of this invention are those which form non-toxicbase salts with the acidic compounds of formula I. Such non-toxic basesalts include those derived from such pharmacologically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmacologicallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction and maximum yields of thedesired final product.

[0072] The compounds of the formula I and the pharmaceuticallyacceptable salts thereof (hereinafter, also referred to, collectively,as “The active compounds of the invention”) are useful for the treatmentof neurodegenerative, psychotropic and drug or alcohol induced deficitsand are potent opioid receptor ligands. The active compounds of theinvention may therefore be used in the treatment of disorders andconditions, such as those enumerated above, that can be treated bymodulatiing binding to an opioid receptor.

[0073] The ability of the compounds of formula I to bind to the variousopioid receptors and their functional activity at such receptors can bedetermined as described below. Binding to the delta opioid receptor canbe determined using procedures well known in the art, such as thosereferred to by Lei Fang et al., J. Pharm. Exp. Ther., 268, 1994, 836-846and Contreras et al., Brain Research, 604, 1993, 160-164.

[0074] In the description of binding and functional assays that follows,the following abbreviations and terminology are used.

[0075] DAMGO is [D-Ala2,N-MePhe4,Gly5-ol]enkephalin).

[0076] U69593 is ((5a, 7a,8b)-(+)—N-methyl-N-(7-[1-pyrrolidinyl]-1-oxasipro[4,5]dec-8-yl)benzeneacetamide).

[0077] SNC-80 is(+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N-diethylbenzamide.

[0078] nor BNI is nor-binaltorphimine.

[0079] CTOP is 1,2-Dithia-5,8,11,14,17-pentaazacycloeicosane, cyclicpeptide derivative DPDPE is [D-en2,D-Pen5]enkephalin).

[0080] [3H]-DAMGO, [3H]-U69593, norBNI, and CTOP are all commerciallyavailable from DuPont, Amersham International, RBI and DuPont, AmershamInternational, RBI and DuPont respectively.

[0081] [3H]-SNC80 was prepared by Amersham International.

[0082] Opioid (mu and kappa) receptor binding assays can be performed inguinea-pig brain membrane preparations. Binding assays can be carriedout at 25° C. for 60 minutes in 50 mM Tris (pH 7.4) buffer. [³H]-DAMGO(2nM) and [³H]-U-69,593 (2 nM) can be used to label mu and kappa receptorbinding sites, respectively. The protein concentration can beapproximately 200 μg/well. Non-specific binding can be defined with 10μM naloxone.

[0083] Delta receptor binding assays can be performed in a stable lineof CHO cells expressing the human delta receptor. The binding assay canbe carried out at 25° C. for 120 minutes in 50 mM Tris (pH 7.4) buffer.[³H]-SNC-80 can be used to label delta receptor binding sites. Theprotein concentration can be approximately 12.5 μg/well. Non-specificbinding can be defined with 10 μM naltrexone.

[0084] The binding reaction can be terminated by rapid filtrationthrough glass fibre filters, and the samples can be washed with ice-cold50 mM Tris buffer (pH 7.4).

[0085] Agonist activity at the delta, mu and kappa opioid receptors canbe determined as follows.

[0086] Opioid (delta, mu and kappa) activity is studied, as describedbelow, in two isolated tissues, the mouse deferens (MVD)(δ) and theguinea-pig myentric plexus with attached longitudinal muscle (GPMP) (μand k).

[0087] MVD (DC1 strain, Charles River, 25-35 g) are suspended in 15 mlorgan baths containing Mg⁺⁺ free Krebs' buffer of the followingcomposition (mM): NaCl, 119; KCl, 4.7; NaHCO₃, 25; KH₂PO₄, 1,2; CaCl₂,2,5 and glucose, 11. The buffer is gassed with 95% O₂ and 5% CO₂. Thetissues are suspended between platinum electrodes, attached to anisometric transducer with 500 mg tension and stimulated with 0.03 Hzpulses of 1-msec pulse-width at supramaximal voltage. IC₅₀ values aredetermined by the regression analysis of concentration-response curvesfor inhibition of electrically-induced contractions in the presence of300 nM of the mu-selective antagonist CTOP. This test is a measure of δagonism.

[0088] Guinea-pig (Porcellus strain, male, 450-500 g, Dunkin Hartley)myentric plexus with attached longitudinal muscle segments are suspendedwith 1 g of tension in Krebs' buffer and stimulated with 0.1 Hz pulsesof 1-msec pulse-width at supramaximal voltage. Mu functional activity isdetermined in the presence of 10 nM nor-BNI with 1 μM of the muselective agonist, DAMGO, added to the bath at the end of the experimentto define a maximal response. This test is a measure of mu agonism.

[0089] Kappa functional activity is determined in the presence of and 1μM CTOP with 1 μM of the kappa selective agonist U-69,593 added at theend of the experiment to define a maximal response. All inhibitions oftwitch height for test compounds are expressed as a percentage of theinhibition obtained with the standard agonist and the corresponding IC₅₀values determined.

[0090] The following procedure can be used to determine the activity ofthe therapeutic agents of this invention as agonists and as antagonistsof delta opioid receptors.

[0091] Cell Culture: Chinese hamster ovary cells expressing the humandelta opioid receptor are passaged twice weekly in Hamis F-12 media withL-glutamine containing 10% fetal bovine serum and 450 μg/mL hygromycin.Cells are prepared for assays 3 days prior to the experiment. 15 mL of0.05% trypsin/EDTA is added to a confluent triple flask, swirled anddecanted to rinse. 15 mL of 0.05% trypsin/EDTA is again added, and theflask is placed into a 37 C incubator for 2 minutes. Cells are removedfrom the flask by banking, and supernatant poured off into a 50 mL tube.30 mL of media is then added to the flask to stop the action of thetrypsin, and then decanted into the 50 mL tube. Tube is then centrifugedfor 5 minutes at 1000 rpm, media decanted, and the pellet resuspendedinto 10 mL of media. Viability of the cells is assessed using trypanblue, the cells counted and plated out into 96 well poly-D-lysine coatedplates at a density of 7,500 cells/well.

[0092] Antagonist Test Plate: Cells plated 3 days prior to assay arerinsed twice with PBS. The plates are placed into a 37 C water bath. 50μL of assay buffer (PBS, dextrose 1 mg/mL, 5 mM MgC12 , 30 mM HEPES,66.7 μg/mL of IBMX) is then added to designated wells. Fifty microlitersof appropriate drug is then added to designated wells, and timed for 1minute. Fifty microliters of 10 μM forskolin+0.4 nM DPDPE (final assayconcentration is 5 μM forskolin, 0.2 nM DPDPE) is then added toappropriate wells, and timed for 15 minutes. The reaction is stopped bythe addition of 10 μL of 6N perchloric acid to all wells. To neutralize,13 μL of 5N KOH is added to all wells, and to stabilize 12 μL of 2MTris, pH 7.4 is added to all wells. Mix by shaking on an orbital shakerfor 10 minutes, and centrifuge at setting 7 for 10 minutes. Alliquotinto 3H plate.

[0093] Agonist Test Plate: Cells plated 3 days prior to assay are rinsedtwice with PBS. The plates are placed into a 37° C. water bath. Fiftymicroliters of assay buffer (PBS, dextrose 1 mg/mL, 5 mM MgCl₂, 30 mMHEPES, 66.7 μg/mL of IBMX) is then added to designated wells. Fiftymicroliters of appropriate drug+10 μM forskolin (final assayconcentration is 5 μM forskolin) is then added to all wells, and timedfor 15 minutes. The reaction is then stopped by the addition of 10 μL of6N perchloric acid to all wells. To neutralize, 13μ of 5N KOH is addedto all wells, and to stablize 12 μL of 2M Tris, pH 7.4 is added to allwells. Mix by shaking on an orbital shaker for 10 minutes, andcentrifuge at setting 7 for 10 minutes. Alliquot into 3H plate.

[0094] Both test plates are placed into an Amersham 3H cAMP binding kitovernight, and harvested onto GF/B filters previously soaked in 0.5% PEIwith a Skatron using 50 mM Tris HCl pH 7.4 at 4° C. Filtermats can beair-dried overnight then place in bags with 20 ml Betaplatescintillation cocktail and counted on a Betaplate counter for 60 sec persample. Data can be analyzed using Excel.

[0095] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, transdermal (e.g., patch), intranasal, parenteral(e.g., intravenous, intramuscular or subcutaneous) or rectaladministration or in a form suitable for administration by inhalation orinsufflation.

[0096] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycollate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

[0097] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0098] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0099] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0100] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0101] In general, a therapeutically effective daily oral or intravenousdose of the compounds of formula (I) and their salts is likely to rangefrom 0.001 to 50 mg/kg body weight of the subject to be treated,preferably 0.1 to 20 mg/kg. The compounds of the formula (I) and theirsalts may also be administered by intravenous infusion, at a dose whichis likely to range from 0.001-10 mg/kg/hr.

[0102] Tables or capsules of the compounds may be administered singly ortwo or more at a time as appropriate. It is also possible to administerthe compounds in sustained release formulations.

[0103] The physician will determine the actual dosage which will be mostsuitable for an individual patient and it will vary with the age, weightand response of the particular patient. The above dosages are exemplaryof the average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention.

[0104] Alternatively, the compounds of the formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstablisers and preservatives as may be required.

[0105] The following Examples illustrate the preparation of thecompounds of the present invention. Commercial reagents were utilizedwithout further purification. All NMR data were recorded at 250, 300 or400 MHz in deuterochloroform unless otherwise specified and are reportedin parts per million (δ) and are referenced to the deuterium lock signalfrom the sample solvent. All non-aqueous reactions were carried out indry glassware with dry solvents under an inert atmosphere forconvenience and to maximize yields. All reactions were stirred with amagnetic stirring bar unless otherwise stated. Unless otherwise stated,all mass spectra were obtained using chemical impact conditions. Ambientor room temperature refers to 20-25° C.

EXAMPLE 1 N,N-diethyl-4-[4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide

[0106] A. 1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol

[0107] To a solution of 3-bromoanisole (20.9 mL, 0.16 mmol) in THF (150mL) at −78° C. under a nitrogen atmosphere was added n-BuLi (66 mL, 0.16mmol, 2.5M in hexanes) over 10 min. The resulting slurry was stirred at−78° C. for 1 hour. To the mixture was added a solution anN-benzyl-4-piperidinone (27.8 mL, 0.15 mmol) in THF (30 mL). Thereaction was stirred at −78° C. for 2 hours and at room temperature for10 hours. The mixture was poured slowly over ice-water (100 mL) and theaqueous layer was washed with EtOAc (3×50 mL). The combined organicextracts were dried (MgSO₄) and concentrated. The crude residue waspurified by flash chromatography with hexanes/EtOAc (3:1) to afford 42.2g of the alcohol (95% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.22 (comp,6H), 7.07-7.04 (comp, 2H), 6.80-6.77 (m, 1H), 3.80 (s, 1H), 3.58 (s,1H), 2.79 (d, 2H), 2.48 (t, 2H), 2.19-2.13 (comp, 2H), 1.72 (dd, 2H),1.58 (s, 1H); MS (M+1) 298.3.

[0108] B. 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenol

[0109] To a solution of 1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-ol(21.7 g, 73.1 mmol) in (CH₂)₂Cl₂ (200 mL) was added phenol (20.7 g, 220mmol) followed by portionwise addition (highly exothermic) of AlCl₃(29.3 g, 200 mmol). The reaction mixture was heated to reflux for 10hours. The mixture was cooled to room temperature and was slowly pouredinto a mixture of crushed ice (50 mL) and 30% aq. NH₄OH (120 mL). Themixture was stirred vigorously for 20 mininutes and was then filteredthrough celite. The celite cake was washed with CH₂Cl₂ (200 mL). Theorganic layer was separated and the aqueous layer was washed with CH₂Cl₂(3×100 mL). The combined organic layers were dried (MgSO₄) andconcentrated. The crude residue was purified by flash chromatographywith hexanes/EtOAc (1:1) to afford 20.1 g (73% yield) of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenol. ¹HNMR (400 MHz,CD₃OD) δ 7.28-7.20 (comp, 5H), 7.14 (t, 1H), 7.07 (d, 2H), 6.83 (d, 2H),6.76 (s, 1H), 6.70-6.60 (comp, 3H), 3.69 (s, 3H), 3.39 (s, 2H),2.50-2.40 (comp, 4H), 2.39-2.29 (comp, 4H); MS (M+1) 374.2.

[0110] C. Trifluoro-methanesulfonic acid4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester

[0111] To a slurry of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenol (22.3 g, 59.8mmol) in CH₂Cl₂ (200 mL) at 0° C. was added pyridine (9.26 mL, 89.7mmol) followed by dropwise addition of triflic anhydride (15.1 mL, 89.7mmol) over 10 minutes. The reaction mixture was stirred at 0° C. for 1hour and at room temperature for 2 hour. The solution was then cooled to0° C. and 40 mL of cold saturated aqueous NaHCO₃ were added. The organiclayer was separated and the aqueous layer was washed with CH₂Cl₂ (3×50mL). The combined organic layers were dried (MgSO₄) and concentrated.The crude residue was purified by flash chromatography withhexanes/EtOAc (3:1) to afford 22.1 g (75% yield) oftrifluoro-methanesulfonic acid4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester. ¹HNMR(400 MHz, CDCl₃) δ 7.32-7.20 (comp, 8H), 7.14 (d, 2H), 6.84 (d, 1H),6.81 (s, 1H), 6.72 (dd, 1H), 3.77 (s, 3H), 3.41 (s, 2H), 2.55-2.38(comp, 8H); MS (M+1) 505.9.

[0112] D. 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acidmethyl ester

[0113] To a solution of trifluoro-methanesulfonic acid4-[1-benzyl-4-(3-methoxy-phenyl)piperidin-4-yl]-phenyl ester (10.0 g,19.8 mmol) in a Parr pressure bottle in MeOH (69 mL) were added DMSO (62mL) and triethylamine (21.8 mL, 157 mmol). To the reaction mixture wereadded palladium acetate (2.2 g, 9.1 mmol) and 1,3-bis(diphenylphosphino) propane (3.75 g, 9.1 mmol). The mixture was shakenunder 40 psi of CO at 70° C. for 4 hours. The reaction mixture wascooled to room temperature and was diluted with diethyl ether (600 mL).The ether layer was washed with water (5×60 mL), dried (MgSO₄) andconcentrated. The crude residue was purified by flash chromatographywith hexanes/EtOAc (1:1) to afford 6.9 g (85% yield) of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methylester. ¹HNMR (400 MHz, CDCl₃) δ 7.91 (d, 2H), 7.32 (d, 2H), 7.28-7.16(comp, 6H),), 6.82 (d, 1H), 6.79 (s, 1H), 6.68 (dd, 1H), 3.86 (s, 3H),3.74 (s, 3H), 3.38 (s, 2H), 2.47-2.44 (comp, 8H); MS (M+1) 416.2.

[0114] E.4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide

[0115] To a solution of diethyl amine (1.88 mL, 18.2 mmol) in CH₂ClCH₂Cl(7 mL) at room temperature was added a trimethylaluminum (9.1 mL, 18.2mmol, 2M in hexanes) dropwise. The reaction mixture was stirred at roomtemperature for 1 hour. A solution of of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methylester (1.51 g, 3.64 mmol) in (CH₂)₂Cl₂ (6 mL) was added and the reactionmixture was heated to reflux for 14 hours. The solution was then cooled0° C. and sat. aqueous NaHCO₃ (15 mL) was added dropwise. The mixturewas filtered through celite. The celite cake was washed with CH₂Cl₂ (40mL). The organic layer was separated and the aqueous layer was washedwith CH₂Cl₂ (3×30 mL). The combined organic layers were dried (MgSO₄)and concentrated. The crude residue was purified by flash chromatographywith EtOAc to afford 1.4 g (84% yield) of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.28-7.16 (comp, 10H), 6.84-6.80 (comp, 2H),6.68 (dd, 1H), 3.74 (s, 3H), 3.52-3.48 (comp, 2H), 3.39 (s, 2H),3.24-3.21 (comp, 2H), 2.47-2.42 (comp, 8H), 1.22-1.20 (comp, 3H),1.19-1.16 (comp, 3H); MS (M+1) 457.2.

[0116] F. N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide

[0117] To a solution of4-[1-Benzyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide(1.11 g, 2.49 mmol) in acetic acid (8 mL) in a Parr pressure bottle wasadded Pd(OH)₂ (10% on carbon, 0.4 g). The reaction mixture was shakenunder 50 psi of H₂ for 20 hours. The reaction mixture was then filterdthrough celite. The celite cake was washed with EtOAc (250 mL) and theorganic layer was concentrated to remove the acetic acid. The residuewas partitioned between CH₂Cl₂ (10 mL) and 30% aqueous NH₄OH (10 mL).The organic layer was separated and the aqueous layer was washed withCH₂Cl₂ (3×20 mL). The combined organic layers were dried (MgSO₄) andconcentrated to afford 0.74 g ofN,N-Diethyl-4-[4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide (83%yield) which was used with no further purification. ¹HNMR (400 MHz,CD₃CO₂D) δ 7.24-7.06 (comp, 5H), 6.75 (s, 1H), 6.70 (d, 1H), 6.58 (d,1H), 3.49-3.40 (comp, 2H), 3.21-3.15 (comp, 2H), 2.90-2.85 (comp, 4H),2.39-2.33 (comp, 4H), 1.20-1.15 (comp, 3H), 1.08-1.02 (comp, 3H); MS(M+1) 353.2.

[0118] The following compounds were made using the procedures set forthabove in Example 1, starting with a compound analogous to the titlecompound of Example 1A wherein R³ is fluro or methoxy, and adding theappropriate amine reactant in the procedure of Example 1E.

[0119]4-[1-Benzyl-4-(3-methoxy-4-methyl-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.01 (d, 1H), 6.68 (d, 1H), 6.61 (s, 1H), 3.70(s, 3H), 3.41 (s, 2H), 2.18 (s, 3H); MS (M+1) 471.2.

[0120]4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N-methyl-benzamide.¹HNMR (400 MHz, CDCl3) d (400 MHz, CDCl₃) δ 7.62(d, 2H), 6.79 (d, 1H),6.66 (d, 1H), 6.04 (br, 1H), 3.77 (s, 3H), 2.99 (d, 3H); MS (M+1) 415.2.

[0121]4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-2-fluoro-N,N-dimethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.09 (d, 1H), 6.95 (d, 1H), 6.71 (d, 1H), 3.79(s, 3H), 3.09 (s, 3H), 2.89 (s, 3H); MS (M+1) 447.2.

[0122]4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N-ethyl-N-methyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.85-6.79 (comp, 2H), 6.68 (d, 1H), 3.79 (s,3H), 3.4 (s, 2H), 3.12.82 (comp, 3H); MS (M+1) 443.3.

[0123]4-[1-Benzyl-4-(3-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.02 (d, 1H), 6.88 (d, 1H), 6.81 (t, 1H),2.62-2.22 (comp, 8H); MS (M+1) 445.2.

EXAMPLE 2 General Procedure for Reductive Alkylation ofN,N-diethyl-4-[4-(3-hydroxy, fluoro ormethoxy-phenyl)-piperidin-4-yl]-benzamides

[0124] To a solution ofN,N-Diethyl-4-[4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide (1equivalent) in CH₂Cl₂ (0.4M) was added the aldehyde (1.2 equivalents)followed by addition of acetic acid (1.2 equivalents) and NaBH(OAc)₃(1.5 equivalents). The reaction mixture was stirred at room temperaturefor 16 hours. The mixture was then partitioned between equal volumes ofCH₂Cl₂ and sat. aqueous NaHCO₃. The organic layer was separated and theaqueous layer was washed with CH₂Cl₂ (3×). The combined organic layerswere dried (MgSO₄) and concentrated. Purification by flashchromatography afforded the desired tertiary amines in yields rangingfrom 60-95%.

[0125] The following compounds were made using the above procedure ofExample 2, starting with a diarylsubstituted pyridine wherein R³ isfluoro or methoxy and R² is the appropriate amide group.{4-[1-(3-Cyclohexyl-propyl)-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl}-morpholin-4-yl-methanone.¹HNMR (400 MHz, CDCl₃) δ 6.82 (d, 1H), 6.79 (s, 1H), 6.71 (d, 1H), 3.75(s, 3H), 1.79-1.61 (comp, 8H); MS (M+1) 505.3.

[0126]{4-[1-Hexyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl}-morpholin-4-yl-methanone.¹HNMR (400 MHz, CDCl₃) δ 6.81 (d, 1H), 6.79 (d, 1H), 6.68 (d, 1H), 3.75(s, 3H), 1.46-1.41 (comp, 2H), 0.84 (t, 3H); MS (M+1) 465.3.

[0127]N,N-Diethyl-4-[4-(3-methoxy-phenyl)-1-(2-phenyl-propyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.82-6.79 (comp, 2H), 6.66 (d, 1H), 3.77 (s,3H), 2.85 (m, 1H), 1.22 (d, 3H); MS (M+1) 485.3.

[0128]N,N-Diethyl-4-[1-hexyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.18 (t, 1H), 6.82-6.80 (comp, 2H), 6.67 (d,1H), 3.74 (s, 3H), 3.57-3.42 (comp, 2H), 2.26-2.20 (comp, 2H), 0.84 (t,3H); MS (M+1) 451.3.

[0129]4-[1-(3-Cyclohexyl-propyl)-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.81 (d, 1H), 6.76 (s, 1H), 6.68 (d, 1H), 3.73(s, 3H), 3.23-3.19 (comp, 2H), 2.47-2.39 (comp, 2H); MS (M+1) 491.3.

[0130]4-[1-(3-Cyclohexyl-propyl)-4-(3-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.01 (d, 1H), 6.86 (d, 1H), 6.82 (t, 1H),3.59-3.4 (comp, 2H), 2.26-2.20 (comp, 2H); MS (M+1) 479.3

[0131]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-(3-phenyl-propyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.02 (d, 1H), 6.69 (d, 1H), 6.81 (t, 1H),3.33-3.19 (comp, 2H), 2.50 (t, 2H), 1.83-1.71 (comp, 2H); MS (M+1)473.2.

[0132]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-methyl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.02 (d, 1H), 6.85 (d, 1H), 2.61-2.41 (comp,8H), 2.26 (s, 3H); MS (M+1) 369.2.

[0133]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-hexyl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.02 (d, 1H), 6.92-6.80 (comp, 2H), 2.52-2.40(comp, 2H), 1.63-1.45 (comp, 2H), 0.79 (t, 3H); MS (M+1) 439.3.

[0134]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-(4-methyl-benzyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.08 (d, 2H), 7.02 (d, 1H), 6.91 (d, 1H), 3.36(s, 2H), 2.59-2.38 (comp, 8H), 2.31 (s, 3H); MS (M+1) 459.2.

[0135]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.03 (d, 1H), 6.92 (d, 1H), 6.85 (t, 1H),3.59-3.41 (comp, 2H), 1.75-1.59 (comp, 2H); MS (M+1) 439.3.

[0136]N,N-Diethyl-4-[4-(3-fluoro-phenyl)-1-(3-methyl-butyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.02 (d, 1H), 6.93 (d, 1H), 6.83 (t, 1H),3.31-3.19 (comp, 2H), 1.58-1.43- (m, 1H), 1.39-1.29 (comp, 2H), 0.86 (d,6H); MS (M+1) 425.3.

EXAMPLE 3 Alkylation ofN,N-diethyl-4-[4-(3-methoxy-phenyl)-piperidin-4-yl]-benzamide

[0137] To a solution ofN,N-Diethyl-4-[4-(3-methoxy-phenyl)-piperidin-4-yl]-benzamide (1equivalent) in DMF (0.5M) was added K₂CO₃ (3-10 equivalents) and thealkyl or heteroaryl halide (1-5 equivalents). The reaction mixture wasstirred at 60-120° C. for 3-16 hours. The mixture was then cooled toroom temperature and filtered. The filtrate was diluted with diethylether and the ether layer was washed with brine. The organic phase wasdried (MgSO₄) and concentrated. Purification by flash chromatographyafforded the desired amines in yields ranging from 30-85%.

[0138] The following compounds were made using a procedure analogous tothat of Example 3, starting with the appropriate amide group.

[0139]4-[1-Allyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl3) d 7.19 (t, 1H), 6.84-6.80 (comp, 2H), 6.69 (d,1H), 5.88-5.79 (m, 1H), 5.15-5.10 (comp, 2H), 3.75 (s, 3H), 2.95-2.87(comp, 2H); MS (M+1) 407.2.

[0140]4-[1-Cyclopropylmethyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) d 7.18 (t, 1H), 6.85-6.79 (comp, 2H), 6.68 (d,1H), 3.74 (s, 3H), 2.21-2.10 (comp, 2H), 1.88-1.78 (comp, 1H), 1.51-1.39(comp, 2H); MS (M+1) 421.2.

[0141]N,N-Diethyl-4-[4-(3-methoxy-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-benzamide.¹HNMR (400 MHz, CDCl3) d 8.15 (d, 1H), 7.44 (t, 1H), 6.88-6.84 (comp,2H), 6.69 (d, 1H), 6.64 (d, 1H), 6.57 (t, 1H), 3.75 (s, 3H), 3.71-3.56(comp, 4H), 2.58-2.40 (comp, 4H); MS (M+1) 444.4.

[0142]N,N-Diethyl-4-[4-(3-methoxy-phenyl)-1-pyrimidin-2-y-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl3) d 8.27 (d, 2H), 6.88-6.80 (comp, 2H), 6.68 (d,1H), 6.44 (t, 1H), 3.95-3.75 (comp, 4H), 3.74 (s, 3H), 3.30-3.19 (comp,2H); MS (M+1) 445.4.

EXAMPLE 4 Deprotection of Methyl Aryl Ethers

[0143] To a solution of methyl ether (1 equivalent) in CH₂Cl₂ (0.4M) at−78° C. was added a solution of boron tribromide (1-5 equivalents) inCH₂Cl₂ (1.0M) dropwise. The reaction mixture was stirred at −78° C. for1 hour was warmed to room temperature and stirred for an additional 4-6hour. The mixture was quenched with slow addition of water and wasbrought to pH 8 with a saturated water/NH₄OH solution. The aqueous layerwas washed with CH₂Cl₂. The organic phase was dried (MgSO₄) andconcentrated. Purification by flash chromatography afforded the desiredphenols in yields ranging from 60-95%.

[0144] Alternatively, the methyl ethers were deprotected with sodiumhydride and ethane thiol in DMF as follows:

[0145] To a suspension of NaH (10 equivalents) in DMF (0.2M) at roomtemperature was added ethane thiol (10 equivalents) dropwise. Themixture was stirred for 5 minutes. To the reaction mixture was added asolution of the methyl ether (1 equivalent) in DMF (0.2M). The mixturewas heated to 120° C. for 10-16 hours. The reaction was cooled to roomtemperature and was quenched with water. The mixture was diluted withdiethyl ether and the organic layer was washed with brine. The organicphase was dried (MgSO₄) and concentrated. Purification by flashchromatography afforded the desired phenols in yields ranging from60-95%.

[0146] The following compounds were made using the procedure of Example4.

[0147]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-methyl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.72-6.67 (comp, 2H), 6.61 (d, 1H), 3.51-3.41(comp, 2H), 2.24-3.19 (comp, 2H), 1.24 (s, 3H); MS (M+1) 367.1.

[0148]4-[1-Allyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.74-6.65 (comp, 2H), 6.64 (d, 1H), 5.99-5.80(m, 1H), 5.22-5.15 (comp, 2H), 3.35-3.19 (comp, 2H), 3.05-2.95 (comp,2H); MS (M+1) 393.2.

[0149]4-[1-Benzyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.78 (d, 1H), 6.63 (d, 1H), 6.61 (s, 1H), 3.50(comp, 2H), 3.42 (s, 2H), 1.19-1.01 (comp, 3H); MS (M+1) 443.2.

[0150]4-[1-Cyclopropylmethyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.90 (s, 1H), 6.78-6.61 (comp, 2H), 3.30-3.19(comp, 2H), 0.69-0.64 (comp, 2H), 0.33-0.30 (comp, 2H); MS (M+1) 407.2.

[0151]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-phenethyl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.79 (d, 1H), 6.69 (s, 1H), 6.63 (d, 1H),2.81-2.68 (comp, 2H); MS (M+1) 457.2

[0152]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-thiazol-2-ylmethyl-piperidin-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.69 (d, 1H), 7.27 (d, 1H), 7.09 (t, 1H), 6.77(d, 1H), 6.68 (s, 1H), 6.59 (d, 1H), 3.75 (s, 2H); MS (M+1) 450.1.

[0153]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-thiophen-2-ylmethyl-piperidin-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.94-6.91 (comp, 2H), 6.78 (d, 1H), 6.64-6.60(comp, 2H), 3.62 (s, 2H), 3.55-3.45 (comp, 2H); MS (M+1) 449.1.

[0154]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-(4-methyl-benzyl)-piperidin-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.98 (d, 2H), 6.79 (d, 1H), 6.62 (d, 1H), 6.46(s, 1H), 3.32 (s, 3H), 2.29 (s, 3H); MS (M+1) 457.2.

[0155]4-[1-Butyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.74 (d, 1H), 6.66 (s, 1H), 6.61 (d, 1H),1.48-1.39 (comp, 2H), 0.85 (t, 3H); MS (M+1) 409.3.

[0156]4-[1-(3-Cyclohexyl-propyl)-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.78 (s, 1H), 6.72-6.66 (comp, 2H), 1.71-1.54(comp 7H), 0.83-0.72 (comp, 2H); MS (M+1) 477.3.

[0157]N,N-Diethyl-4-[1-hexyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.75 (d, 1H), 6.70 (s, 1H), 6.64 (d, 1H),1.59-1.41 (comp, 2H), 0.84 (t, 3H); MS (M+1) 437.3.

[0158]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-(3-methyl-butyl)-piperidin-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ6.76 (s, 1H), 6.71 (d, 1H), 6.67 (d, 1H), 0.87(d, 3H); MS (M+1) 423.3

[0159]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-isobutyl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 6.74 (d, 1H), 6.69 (s, 1H), 6.60 (d, 1H),2.11-2.02 (comp, 2H), 1.80-1.73 (m, 1H), 0.86 (d, 6H); MS (M+1) 409.3.

[0160]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-(4-isopropyl-benzyl)-piperidin-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.08 (t, 1H), 7.01 (d, 1H), 6.74 (d, 1H), 6.62(d, 1H), 6.56 (s, 1H), 3.40 (s, 2H), 2.88-2.79 (m, 1H), 1.20 (d, 6H); MS(M+1) 485.3.

[0161]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]benzamide.¹HNMR (400 MHz, CDCl₃) δ 8.17-8.12 (m, 1H), 7.52-7.45 (m, 1H), 6.81-6.72(comp, 2H), 6.66 (d, 1H), 6.61-6.55 (comp, 2H), 3.70-3.42 (comp, 6H); MS(M+1) 430.4.

[0162]N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-1-pyrimidin-2-yl-piperidin-4-yl]-benzamide.¹HNMR (400 MHz, CDCl₃) δ 8.27 (comp, 2H), 6.57 (s, 1H), 6.44 (d, 1H),3.91-3.85 (comp, 2H), 3.78-3.69 (comp, 2H), 3.51-3.47 (comp, 2H); MS(M+1) 431.3.

[0163]4-[1-Benzooxazol-2-yl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.34 (d, 1H), 7.02 (t, 1H), 6.81-7.74 (comp,2H), 6.62 (dd, 1H), 3.81-3.71 (comp, 2H), 3.69-3.60 (comp, 2H); MS (M+1)470.3.

[0164]4-[4-(3-Hydroxy-phenyl)-1-(4-methyl-benzyl)-piperidin-4-yl]-N,N-dimethylbenzamide.¹HNMR (400 MHz, CDCl₃) δ7.07 (d, 2H), 6.75 (d, 1H), 6.61 (d, 1H), 6.45(s, 1H), 3.34 (s, 2H), 3.05 (s, 3H), 2.92 (s, 3H), 2.27 (s, 3H); MS(M+1) 429.3.

[0165]4-[4-(3-Hydroxy-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-N,N-dimethylbenzamide.¹HNMR (400 MHz, CDCl₃) δ 7.09 (t, 1H), 6.76 (d, 1H), 6.68 (s, 1H), 3.07(s, 3H), 1.1-098 (m, 1H), 0.88-0.82 (comp, 6); MS (M+1) 409.3.

[0166]4-[4-(3-Hydroxy-phenyl)-1-(3-methyl-butyl)-piperidin-4-yl]-N,N-dimethylbenzamide.¹HNMR (400 MHz, CDCl₃) δ 7.20-7.05 (comp, 3H), 6.77 (s, 1H), 3.06 (s,3H), 2.94 (s, 3H), 0.84 (d, 6H); MS (M+1) 395.3.

[0167]{4-[1-(4-Fluoro-benzyl)-4-(3-hydroxy-phenyl)-piperidin-4-yl]-phenyl}-piperidin-1-yl-methanone.¹HNMR (400 MHz, CDCl₃) δ 6.96 (t, 2H), 6.78 (d, 1H), 6.61 (dd, 1H), 6.51(s, 1H), 3.72-3.59 (comp, 2H), 3.36 (s, 2H), 3.35-3.31 (comp, 2H); MS(M+1) 473.2.

[0168]{4-[1-Hexyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-phenyl}-morpholin-4-yl-methanone.¹HNMR (400 MHz, CDCl₃) δ7.09 (t, 1H), 6.75 (d, 1H), 6.64 (s, 1H), 6.60(d, 1H), 3.86-3.22 (comp, 8H)0.83 (t, 3H); MS (M+1) 451.3.

EXAMPLE 5 Trifluoro-methanesulfonic acid3-[1-Benzyl-4-(4-diethylcarbamoyl-phenyl)-piperidin-4-yl]-phenyl ester

[0169] To a solution of4-[1-Benzyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamidein CH₂Cl₂ (14 mL) at 0° C. was added pyridine (0.43 mL, 5.33 mmol)followed by dropwise addition of triflic anhydride (0.9 mL, 5.33 mmol)over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour andat room temperature for 2 hours. The solution was then cooled to 0° C.and 15 mL of cold saturated aqueous NaHCO₃ were added. The organic layerwas separated and the aqueous layer was washed with CH₂Cl₂ (3×20 mL).The combined organic layers were dried (MgSO₄) and concentrated. Thecrude residue was purified by flash chromatography with hexanes/EtOAc(4:1) to afford 1.57 g (77% yield) of trifluoro-methanesulfonic acid3-[1-benzyl-4-(4-diethylcarbamoyl-phenyl)-piperidin-4-yl]-phenyl ester.¹HNMR (400 MHz, CDCl₃) δ 7.42-7.20 (comp, 11H), 7.15-7.02 (comp, 2H),3.63-3.43 (comp, 2H), 3.42 (s, 2H), 3.35-3.29 (comp, 2H), 2.8-2.39(comp, 8H), 1.31-1.21 (comp, 3H), 1.21-1.08 (comp, 3H); MS (M+1) 575.2.

EXAMPLE 64-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide

[0170] To a solution of trifluoro-methanesulfonic acid3-[1-benzyl-4-(4-diethylcarbamoylphenyl)-piperidin-4-yl]-phenyl ester(1.82 g, 3.16 mmol) in DMF (14 mL) was added zinc cyanide (0.26 g, 2.21mmol) and tetrakis triphenylphosphine palladium (0.73 g, 0.63 mmol). Thereaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours.The mixture was cooled to room temperatures and it was diluted withdiethyl ether (100 mL). The organic layer was washed with brine (5×10mL), dried (MgSO₄) and concentrated. Purification with hexanes/EtOAc(1:1) afforded 1.3 g (91% yield) of4-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.69-7.20 (comp, 13H), 3.55-3.43 (comp, 2H),3.41 (s, 2H), 3.31-3.19 (comp, 2H), 2.6-2.25 (comp, 8H), 1.28-1.19(comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.

EXAMPLE 7

[0171]

4-[1-Benzyl-4-(3-carboxamido-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide

[0172] To a solution of4-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide(0.11 g, 0.24 mmol) in ethanol (0.3 mL) was added 3N aqueous Na₂CO₃ (0.6mL) and 30% aqueous H₂O₂ (0.15 mL). The reaction mixture was stirred atroom temperature for 8 hours. The mixture was diluted with water (2 mL)and the aqueous layer was washed with CH₂Cl₂ (3×5 mL). The organic layerwas dried (MgSO₄) and concentrated. The residue was purified by flashchromatography with CH₂Cl₂/MeOH (10:1) to afford 35 mg (31% yield) of4-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.55-7.20 (comp, 12H), 6.13 (br,1H), 5.62 (br, 1H), 3.48-3.40 (comp, 2H), 3.38 (s, 2H), 3.23-3.19 (comp,2H), 2.51-2.39 (comp, 8H)1.27-1.20 (comp, 3H), 1.15-1.07 (comp, 3H); MS(M+1) 470.3.

EXAMPLE 81-Benzyl-4-(3-methoxy-phenyl)-4-(4-thiophen-2-yl-phenyl)-piperidine

[0173] To a solution of trifluoro-methanesulfonic acid4-[1-benzyl-4-(3-methoxy-phenyl)piperidin-4-yl]-phenyl ester (0.1 g, 0.2mmol) in ethanol (4.5 mL) and water (0.5 mL) was added 2-thiopheneboronic acid (0.052 g, 0.5 mmol) and sodium carbonate (0.037 g, 0.29mmol) and tetrakis tripheny;phosphine palladium (0.02 g, 0.18 mmol). Thereaction mixture was heated to reflux for 2 hours. The mixture was thenfiltered and the filtrate was concentrated under vacuum. The residue waspurified by flash chromatography with hexanes/EtOAc (3:1) to afford 0.08g (92% yield) of1-Benzyl-4-(3-methoxy-phenyl)-4-(4-thiophen-2-yl-phenyl)-piperidine.¹HNMR (400 MHz, CDCl₃) δ 7.50 (d, 2H), 7.33-7.18 (comp, 10H), 7.07-7.00(m, 1H), 6.89-6.63 (comp, 2H), 6.69 (d, 1H), 3.76 (s, 3H), 3.42 (s, 2H),2.61-2.39 (comp, 8H); MS (M+1) 440.2.

[0174] The following compounds were made using a procedure analogous tothat of Example 8, starting with the appropriate ester wherein R³ ismethoxy, hydroxy or fluoro.

[0175] 3-[1-Benzyl-4-(4-thiophen-2-yl-phenyl)-piperidin-4-yl]-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.46 (d, 2H), 7.16 (d, 2H), 6.80 (d, 1H), 6.59(dd, 1H), 6.54 (s, 1H), 3.40 (s, 2H); MS (M+1) 426.0.

[0176]3-[1-Benzyl-4-(4′-trifluoromethyl-biphenyl-4-yl)-piperidin-4-yl]-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.67-7.58 (comp, 4H), 7.44 (d, 2H), 7.12 (t,1H), 6.80 (d, 1H), 6.62-6.59 (comp, 2H); MS (M+1) 488.2.

[0177] 3-[1-Benzyl-4-(4′-methyl-biphenyl-4-yl)-piperidin-4-yl]-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.45-7.40 (comp, 4H), 7.11 (t, 1H), 6.77 (d,1H), 6.56 (s, 1H), 3.44 (s, 2H); MS (M+1) 434.3

[0178]3-[1-Benzyl-4-(3′-chloro-4′-fluoro-biphenyl-4-yl)-piperidin-4-yl]-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.54 (dd, 1H), 7.20-7.11 (comp, 2H), 6.80 (d,1H), 6.65 (s, 1H), 6.62 (d, 1H), 3.44 (s, 2H); MS (M+1) 472.1.

EXAMPLES 9 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile

[0179] To a solution of trifluoro-methanesulfonic acid4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester (2.2 g,4.34 mmol) in DMF (8 mL) was added zinc cyanide (0.61 g, 5.22 mmol) andtetrakis triphenylphosphine palladium (0.7 g, 0.63 mmol). The reactionwas stirred under a nitrogen atmosphere at 90° C. for 5 hours. Themixture was cooled to room temperature and it was diluted with diethylether (100 mL). The organic layer was washed with brine (5×10 mL), dried(MgSO₄) and concentrated. Purification with hexanes/EtOAc (2:1) afforded1.52 g (92% yield) of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile. ¹HNMR(400 MHz, CDCl₃) δ 7.51 (d, 2H), 7.34 (d, 2H), 7.28-7.18 (comp, 6H),6.80 (d, 1H), 6.77 (s, 1H), 6.70(d, 1H), 3.75 (s, 3H), 3.39 (s, 2H),2.63-2.39 (comp, 8H); MS (M+1) 383.2.

EXAMPLE 101-Benzyl-4-(3-methoxy-phenyl)-4-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine

[0180] To a solution of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile (0.24 g,0.63 mmol) in toluene (5 mL) were added dibutyltin oxide (0.025 g, 0.1mmol) and trimethylsilyl azide (0.15 g, 1.26 mmol). The reaction mixturewas heated for 60 hours. The mixture was then cooled to room temperatureand concentrated under vacuum. The residue was dissolved in methanol (5mL) and then concentrated. The residue was partitioned between saturatedaqueous sodium bicarbonate solution (5 mL) and ethyl acetate. Theaqueous layer was washed with ethyl acetate (3×10 mL). The combinedextracts were dried (MgSO₄) and concentrated. Purification by flashchromatography with CH₂Cl₂/MeOH (9:1) afforded 0.19 g (71% yield) of1-Benzyl-4-(3-methoxy-phenyl)-4-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine.¹HNMR (400 MHz, CD₃OD) δ 7.95 (d, 2H), 7.44-7.41 (comp, 7H), 7.23-7.18(m, 1H), 6.90-6.77 (comp, 2H), 6.76 (d, 1H), 6.70 (d, 1H), 4.21 (s, 2H),3.64 (s, 3H), 3.30-2.41 (comp, 8H); MS (M+1) 426.2.

EXAMPLE 111-Benzyl-4-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine

[0181] To a solution of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N-methyl-benzamide(1.01 g, 2.44 mmol), in CH₂Cl₂ (24 mL) was added pyridine (0.30 mL, 3.71mmol). The reaction was cooled to −50 C and triflic anhydride (0.45,2.67 mmo) was added dropwise over 1 minutes. The reaction was stirred at−50° C. for 1.5 hours and at room temperature for 0.5 hours. The mixturewas cooled to −50° C. and 2-amino-2-methyl propanol (0.36 mL, 3.77 mmol)was added. The reaction was allowed to warm to room temperature andstirred at room temperature for 16 hours. To the mixture was added water(5 mL) and the aqueous layer was extracted with CH₂Cl₂ (3×15 mL). Thecombined extracts were dried (MgSO₄) and concentrated. Purification byflash chromatography with hexanes/EtOAc (1:1) afforded 0.75 g (68%yield) of1-Benzyl-4-[4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine.¹HNMR (400 MHz, CDCl₃) δ; 7.83 (d, 2H), 7.38-7.21 (comp, 7H), 7.18 (t,1H), 6.81-6.75 (comp, 2H), 6.63 (d, 1H), 4.08 (s, 2H), 3.78 (s, 3H),3.41 (s, 2H), 2.79-2.40 (comp, 8H), 1.38 (s, 3H); MS (M+1) 454.2.

EXAMPLE 122-{4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl}-propan-2-ol

[0182] To a solution of4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methylester (3.3 g, 7.95 mmol) in THF (30 mL) at 0° C. was added methylmagnesium bromide (3M in diethyl ether, 10.6 mL, 31.8 mmol). The icebath was removed and the reaction was stirred at room temperature for 5hours and at 50° C. for 5 hours. The mixture was cooled to roomtemperature and was quenched with slow addition of water (15 mL). Theaqueous layer was washed with diethyl ether (3×30 mL). The combinedextracts were dried (MgSO₄) and concentrated. Purification by flashchromatography with hexanes/EtOAc afforded 3.1 g (94%) of2-{4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl}-propan-2-ol.¹HNMR (400 MHz, CDCl₃) δ 7.38-7-08 (comp, 10H), 6.81 (d, 1H), 6.61-6.59(comp, 2H), 3.8 (s, 3H), 3.6 (s, 2H), 2.52-2.23 (comp, 8H), 1.42 (s,6H); MS (M+1) 415.2.

[0183] The following compound was prepared by a procedure analogous tothat of Example 12.

[0184]3-{4-[1-Benzyl-4-(3-fluoro-5-methoxy-phenyl)-piperidin-4-yl]-2-fluoro-phenyl}-pentan-3-ol.¹HNMR (400 MHz, CDCl₃) δ 7.36 (d, 2H), 7.18 (d, 2H), 6.61 (s, 1H), 6.39(d, 1H), 3.73 (s, 3H), 1.54 (s, 6H); MS (M+1) 434.0.

[0185] The following phenol derivatives were made using a procedureanalogous to that of Example 12, followed by deprotection using theprocedure of Example 4.

[0186]3-{1-(3-Cyclohexyl-propyl)-4-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperidin-4-yl}-phenol.¹HNMR (400 MHz, CDCl₃) δ 6.74 (d, 1H), 6.63 (s, 1H), 6.58 (d, 1H),2.21-2.18 (comp, 2H), 1.68-1.57 (comp, 4H), 0.82-0.79 (comp, 2H); MS(M+1) 436.3.

[0187]3-{1-Benzyl-4-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperidin-4-yl}-phenol.¹HNMR (400 MHz, CDCl₃) δ 6.80 (d, 1H), 6.60-6.51 (comp, 2H), 3.39 (s,2H), 2.55-2.18 (comp, 4H); MS (M+1) 402.2.

[0188]3-{1-Benzyl-4-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperidin-4-yl}-5-fluoro-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.06 (d, 2H), 6.46 (s, 1H), 6.42-6.30 (comp,2H), 3.55 (s, 2H), 1.52 (s, 6H); MS (M+1) 420.1.

EXAMPLE 13 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acidhydrazide

[0189] To a solution of4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methylester (9.5 g, 22.9 mmol) in methanol (60 mL) was added hydrazine hydrate(8 mL). The reaction mixture was heated to reflux for 36 hours. Themixture was cooled to room temperature and concentrated. The residue wasdissolved in toluene (50 mL) and concentrated under vacuum, and4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazidewas obtained in quantitative yield. The residue was used in thesubsequent steps without purification. ¹HNMR (400 MHz, CD₃OD) δ 7.82 (d,1H), 7.67 (d, 1H), 7.39-7.05 (comp, 8H), 6.86 (d, 1H), 6.80 (s, 1H),6.67 (d, 1H), 3.69 (s, 3H), 3.38 (s, 2H), 2.62-2.37 (comp, 8H); MS (M+1)416.3.

EXAMPLE 14 Cyclobutanecarboxylic AcidN′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide

[0190] To a solution of4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide(0.7 g, 1.69 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added triethylamine(0.35 mL, 2.5 mmol) was catalytic DMAP (20 mg) and cyclobutane carbonylchloride (0.19 mL, 1.69 mmol). The mixture was stirred at 0° C. for 1hour and at room temperature for 5 hours. The solution was washed withbrine (5 mL), dried (MgSO₄) and concentrated. Purification by flashchromatography with hexanes/EtOAc (6:4) afforded 0.63 g (75% yield) ofcyclobutanecarboxylic acidN′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}hydrazide.¹HNMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 7.67 (d, 2H), 7.41-7.08 (comp,8H), 6.82-6.61 (comp, 3H), 3.79 (s, 3H), 2.41 (s, 2H), 3.09-3.02 (m,1H), 2.41-2.23 (comp, 8H), 2.19-1.67 (comp, 6H); MS (M+1) 498.2.

EXAMPLE 151-Benzyl-4-[4-(5-cyclobutyl-[1,3,4]oxadiazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine

[0191] To a solution of cyclobutanecarboxylic acidN′-{4-[1-benzyl-4-(3-methoxy-phenyl)piperidin-4-yl]-benzoyl}-hydrazide(0.2 g, 0.40 mmol) in CH₂Cl₂ (3 mL) was added pyridine (0.08 mL, 1.0mmol). The reaction mixture was cooled to −78° C. Triflic anhydride(0.14 mL, 0.84 mmol) was added dropwise. The mixture was stirred at −78°C. for 1 hour and at room temperature for 2 hours. The reaction wasquenched with saturated aqueous sodium bicarbonate (3 mL). The aqueouslayer was washed with CH₂Cl₂ (3×5 mL) and the combined extracts weredried (MgSO₄) and concentrated. Purification by flash chromatograpy withEtOAc afforded 0.19 g (quantitative yield) of1-Benzyl-4-[4-(5-cyclobutyl-[1,3,4]oxadiazol-2-yl)phenyl]-4-(3-methoxy-phenyl)-piperidine.¹HNMR (400 MHz, CDCl₃) δ 7.92 (d, 2H), 7.37 (d, 2H), 7.36-7.16 (comp,6H), 6.83 (d, 1H), 6.80 (s, 1H), 6.60 (d, 1H), 3.81-3.78 (m, 1H), 3.77(s, 3H), 3.45 (s, 2H), 2.82-2.38 (comp, 10H), 2.21-2.19 (comp, 2H); MS(M+1) 480.2.

[0192] The following compound was made using a procedure analogous tothat of Example 15.

[0193]1-Benzyl-4-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine.¹HNMR (400 MHz, CDCl₃) δ 7.92-7.81 (comp, 2H), 6.83 (d, 1H), 6.79 (s,1H), 6.71-6.65 (m, 1H), 3.74 (s, 3H), 2.20-2.14 (m, 1H); MS (M+1) 466.4.

[0194] The following phenol derivatives were made using the procedure ofExample 15, followed by deprotection using the procedure of Example 4.

[0195]3-{1-Benzyl-4-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperidin-4-yl)-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.79 (d, 2H), 7.41-7.37 (comp, 2H), 7.12 (t,1H), 3.63 (s, 2H), 2.57 (s, 3H); MS (M+1) 426.3.

[0196]3-(1-Benzyl-4-[4-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl]phenyl}-piperidin-4-yl)phenol.¹HNMR (400 MHz, CDCl₃) δ 7.88-7.72 (comp, 2H), 7.56-7.42 (comp, 2H),6.91-6.84 (m, 1H), 6.69-6.63 (m, 1H), 3.86 (s, 2H), 2.21-2.16 (m, 1H);MS (M+1) 452.2.

[0197]3-{1-Benzyl-4-[4-(5-ethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperidin-4-yl}-phenol.¹HNMR (400 MHz, CDCl₃) δ 7.79 (d, 2H), 7.11 (t, 1H), 7.75 (d, 1H), 6.65(d, 1H), 6.55 (s, 1H), 2.90 (q, 2H), 1.38 (t, 3H); MS (M+1) 440.4.

[0198]3-{1-Benzyl-4-[4-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperidin-4-yl}phenol.¹HNMR (400 MHz, CDCl₃) δ 7.91 (d, 2H), 7.32 (d, 2H), 7.12 (t, 1H), 6.75(d, 1H), 6.63-6.60 (comp, 2H), 3.42 (s, 2H); MS (M+1) 480.2.

EXAMPLE 16 Additional Synthetic Pathways

[0199]

1. A compound of the formula

R¹ is hydrogen, (C₀-C₈)alkoxy-(C₀-C₈)alkyl-, wherein the total number ofcarbon atoms is eight or less, aryl, aryl-(C₁-C₈)alkyl-, heteroaryl,heteroaryl-(C₁-C₈)alkyl-, heterocyclic, heterocyclic-(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl-, or (C₃-C₇)cycloalkyl-(C₁-C₈)alkyl, wherein said aryland the aryl moiety of said aryl-(C₁-C₈)alkyl- are selected,independently, from phenyl and napthyl, and wherein said heteroaryl andthe heteroaryl moiety of said heteroaryl-(C₁-C₈)alkyl- are selected,independently, from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl,pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl,xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolyl, oxadiazoyl, isoxazoyl, thiazolyl,isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl,thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein saidheterocyclic and the heterocyclic moiety of saidheterocyclic-(C₁-C₈)alkyl- are selected from saturated or unsaturatednonaromatic monocyclic or bicyclic ring systems, wherein said monocyclicring systems contain from four to seven ring carbon atoms, from one tothree of which may optionally be replaced with O, N or S, and whereinsaid bicyclic ring systems contain from seven to twelve ring carbonatoms, from one to four of which may optionally be replaced with O, N orS; and wherein any of the aryl, heteroaryl or heterocyclic moieties ofR¹ may optionally be substituted with from one to three substitutuents,preferably with one or two substutituents, independently selected fromhalo (i.e., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionallysubstituted with from one to seven (preferably with from zero to four)fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino, and whereinany of alkyl moieties in R¹ (e.g., the alkyl moieties of alkyl, alkoxyor alkylamino groups) may optionally be substituted with from one toseven (preferably with from zero to four) fluorine atoms; R² ishydrogen, aryl, heteroaryl, heterocyclic, SO₂R⁴, COR⁴, CONR⁵R⁶, COOR⁴,or C(OH)R⁵R⁶ wherein each of R⁴, R⁵ and R⁶ is defined, independently, asR¹ is defined above, or R⁵ and R⁶, together with the carbon or nitrogento which they are both attached, form a three to seven memberedsaturated ring containing from zero to three heterocarbons selected,independently, from O, N and S, and wherein said aryl, heteroaryl, andheterocyclic are defined as such terms are defined above in thedefinition of R¹, and wherein any of the aryl, heteroaryl andheterocyclic moieties of R² may optionally be substituted with from oneto three substitutuents, preferably with one or two substutituents,independently selected from halo (i.e., chloro, fluoro, bromo or iodo),(C₁-C₆)alkyl optionally substituted with from one to seven (preferablywith from zero to four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl,amino, cyano, nitro, (C₁-C₆)alkoxy optionally substituted with from oneto seven (preferably with from zero to four) fluorine atoms,(C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino; R³ is hydroxy, NHSO₂R⁷,C(OH)R⁷R⁸, fluorine or CONHR⁷, wherein R⁷ and R⁸ are the same ordifferent and are selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxyand (C₁-C₄)alkoxy-(C₁-C₄)alkyl having a total of 4 or less carbon atoms,and wherein any of the alkyl moieties of R⁷ and R⁸ may optionally besubstituted with from one to seven (preferably with from zero to four)fluorine atoms; and Z¹ and Z² are selected independently, from hydrogen,halo and (C₁-C₅)alkyl; with the proviso that there are no two adjacentring oxygen atoms and no ring oxygen atom adjacent to either a ringnitrogen atom or a ring sulfur atom in any of the heterocyclic orheteroaryl moieties of formula I; or a pharmaceutically acceptable saltof such compound.
 2. A compound according to claim 1 wherein R⁵ and R⁶are selected, independently, from the groups set forth in the definitionof R⁷ and R⁸.
 3. A compound according to claim 1 wherein R¹ iscyclopropylmethyl, 3-cyclohexylpropyl, 2-phenylethyl, 2-methylpentyl,p-methylbenzyl, 2,2,2-trifluoroethyl, or 1-methylpentyl.
 4. A compoundaccording to claim 2 wherein R¹ is cyclopropylmethyl,3-cyclohexylpropyl, 2-phenylethyl, 2-methylpentyl, p-methylbenzyl,2,2,2-trifluoroethyl, or 1-methylpentyl.
 5. A compound according toclaim 1 wherein R² is methyl ethyl amide, diethyl amide, a diethylcarbinol, tetrazole, or pyrazole.
 6. The compound according to claim 2wherein R² is methyl ethyl amide, diethyl amide, a diethyl carbinol,tetrazole, or pyrazole.
 7. A compound according to claim 1 wherein R³ ishydroxy, fluoro, CONH₂, NHSO₂CH₃, or methoxy.
 8. A compound according toclaim 2 wherein R³ is hydroxy, fluoro, CONH₂, NHSO₂CH₃, or methoxy.
 9. Apharmaceutical composition for treating a disorder or condition selectedfrom inflammatory diseases such as arthritis, psoriasis, asthma, orinflammatory bowel disease, disorders of respiratory function such asasthma, cough and apnea, allergies, gastrointestinal disorders such asgastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distension, functional pain,nonulcerogenic dyspepsia and other disorders of motility or secretion,and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma,cerebral ischemia, cerebral deficits subsequent to cardiac bypasssurgery and grafting, urogential tract disorders such as urinaryincontinence, chemical dependencies and addictions (e.g., addictions toor dependencies on alcohol, opiates, benzodiazepines, nicotine, heroinor cocaine), chronic pain, nonsomatic pain, acute pain and neurogenicpain, systemic lupus erythematosis, Hodgkin's disease, Sjogren'sdisease, epilepsy and rejection in organ transplants and skin grafts ina mammal, comprising an amount of a compound according to claim 1 thatis effective in treating such disorder or condition and apharmaceutically acceptable carrier.
 10. A pharmaceutical compositionfor treating a disorder or condition, the treatment or prevention ofwhich can be effected or facilitated by modulating binding to opioidreceptors in a mammal, comprising an amount of a compound according toclaim 1 that is effective in treating such disorder or condition and apharmaceutically acceptable carrier.
 11. A method for treating adisorder or condition selected from inflammatory diseases such asarthritis, psoriasis, asthma, or inflammatory bowel disease, disordersof respiratory function such as asthma, cough and apnea, allergies,gastrointestinal disorders such as gastritis, functional bowel disease,irritable bowel syndrome, functional diarrhoea, functional distension,functional pain, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, stroke, shock, brain edema, headtrauma, spinal cord trauma, cerebral ischemia, cerebral deficitssubsequent to cardiac bypass surgery and grafting, urogential tractdisorders such as urinary incontinence, chemical dependencies andaddictions (e.g., addictions to or dependencies on alcohol, opiates,benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomaticpain, acute pain and neurogenic pain, systemic lupus erythematosis,Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organtransplants and skin grafts in a mammal, comprising administering to amammal requiring such treatment an amount of a compound according toclaim 1 that is effective in treating such disorder or condition.
 12. Amethod for treating a disorder or condition, the treatment of which canbe effected or facilitated by modulating binding to opioid receptors ina mammal, comprising administering to a mammal requiring such treatmentan amount of a compound according to claim 1 that is effective intreating such disorder or condition.
 13. A pharmaceutical compositionfor treating a disorder or condition selected from inflammatory diseasessuch as arthritis, psoriasis, asthma, or inflammatory bowel disease,disorders of respiratory function such as asthma, cough and apnea,allergies, gastrointestinal disorders such as gastritis, functionalbowel disease, irritable bowel syndrome, functional diarrhoea,functional distension, functional pain, nonulcerogenic dyspepsia andother disorders of motility or secretion, and emesis, stroke, shock,brain edema, head trauma, spinal cord trauma, cerebral ischemia,cerebral deficits subsequent to cardiac bypass surgery and grafting,urogential tract disorders such as urinary incontinence, chemicaldependencies and addictions (e.g., addictions to or dependencies onalcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronicpain, nonsomatic pain, acute pain and neurogenic pain, systemic lupuserythematosis, Hodgkin's disease, Sjogren's disease, epilepsy andrejection in organ transplants and skin grafts in a mammal, comprisingan opioid receptor binding modulating effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 14. Apharmaceutical composition for treating a disorder or condition, thetreatment or prevention of which can be effected or facilitated bymodulating binding to opioid receptors in a mammal, comprising an opioidreceptor binding modulating effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 15. A method fortreating a disorder or condition selected from inflammatory diseasessuch as arthritis, psoriasis, asthma, or inflammatory bowel disease,disorders of respiratory function such as asthma, cough and apnea,allergies, gastrointestinal disorders such as gastritis, functionalbowel disease, irritable bowel syndrome, functional diarrhoea,functional distension, functional pain, nonulcerogenic dyspepsia andother disorders of motility or secretion, and emesis, stroke, shock,brain edema, head trauma, spinal cord trauma, cerebral ischemia,cerebral deficits subsequent to cardiac bypass surgery and grafting,urogential tract disorders such as urinary incontinence, chemicaldependencies and addictions (e.g., addictions to or dependencies onalcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronicpain, nonsomatic pain, acute pain and neurogenic pain, systemic lupuserythematosis, Hodgkin's disease, Sjogren's disease, epilepsy andrejection in organ transplants and skin grafts in a mammal, comprisingadministering to a mammal requiring such treatment an opioid receptorbinding modulating effective amount of a compound according to claim 1.16. A method for treating a disorder or condition, the treatment orprevention of which can be effected or facilitated by modulating bindingto opioid receptors in a mammal, comprising administering to a mammalrequiring such treatment an opioid receptor binding modulating effectiveamount of a compound according to claim 1.